Osteoporosis is a crippling bone disease that poses a major public health problem. Around 44 million Americans, both men and women, suffer from the disease. It is silent and hence, most often under-diagnosed. It causes fractures, most notably hip, spinal and wrist fractures that result in disability and death.
Osteoporosis in women after the menopause is thought to result from low estrogen levels that accompany ovarian failure. It has been shown that estrogen can directly control excessive bone removal by its action on the osteoclast, a cell unique in its ability to resorb bone. Normally, the activity of the osteoclast is tightly coupled to that of the osteoblast, a cell that forms new bone. When osteoclastic bone resorption is in excess of bone formation, more bone is lost than is gained with resulting gaps in bone, which becomes prone to fracture and collapse.
There is convincing evidence that the post-menopausal increase in bone resorption results from an absolute increase in number of osteoclasts resident in bone, rather than from the enhanced activity of individual cells. This is due to the increased recruitment of new osteoclasts from bone marrow. Replacement of estrogen corrects this defect, and it has thus been speculated that declining estrogen levels are solely responsible for the increased osteoclastogenesis and post-menopausal bone loss.
Follicle-stimulating hormone (FSH) is a glycoprotein hormone synthesized and secreted by the pituitary. It causes the synthesis and secretion of estrogen by interacting with its receptor, the FSH receptor, on the follicular cell of the ovary. Estrogen levels, in turn, control FSH release from the pituitary through a well-known feedback mechanism. Thus, when estrogen rises, FSH falls. Likewise, when the ovaries fail during menopause, FSH levels rise. FSH has, however, never been implicated directly in causing post-menopausal bone loss, although serum FSH levels have been shown to correlate with bone remodeling increases in women (Kawai et al, 2004; Sowers et al, 2003).
Thus, estrogen depletion may not completely explain post-menopausal bone remodeling. Accordingly, there exists a need in the art for identification of additional factors that contribute to osteoporosis and other osteoclast-mediated disease characterized by bone loss.